Compositions for the treatment of hypertension and/or fibrosis

ABSTRACT

The present invention relates to novel compounds and their use in the prophylactic and/or therapeutic treatment of hypertension and/or fibrosis.

The present application is a divisional application of U.S. patentapplication Ser. No. 16/334,283, filed Mar. 18, 2019, allowed Mar. 10,2021, which is a U.S. National Stage Entry of PCT/AU2017/051027, filedSep. 21, 2017, claims priority from Australian Provisional PatentApplication No. 2016903804, filed Sep. 21, 2016, the contents of whichare incorporated in their entirety herein.

FIELD OF THE INVENTION

The present invention relates to novel compounds and their use in theprophylactic and/or therapeutic treatment of cardiovascular disease, andin particular the treatment of prehypertension, hypertension and/orfibrotic conditions.

The invention has been developed primarily for the prophylactic and/ortherapeutic treatment of cardiovascular disease and will be describedhereinafter with reference to this application. However, it will beappreciated that the invention is not limited to this particular fieldof use.

BACKGROUND OF THE INVENTION

Any discussion of the prior art throughout the specification should inno way be considered as an admission that such prior art is widely knownor forms part of the common general knowledge in the field.

Hypertension (high blood pressure) affects 26% of the adult populationworldwide with an incidence of 30-33% in western countries. The worldwide incidence of hypertension is expected to reach 29% by 2025 as aconsequence of the westernisation of India and China. Current studiesindicate that fewer than 20% of patients with hypertension attain theirrecommended blood pressure (BP) target and that to achieve thesetargets >75% of patients require therapy with multiple antihypertensiveagents. Prehypertension (slightly elevated blood pressure) affects 31%of adults in the US and may develop into hypertension if not treated.

Hypertension and prehypertension are a major factor in the developmentof blood vessel damage in a variety of organs, resulting in thereplacement of normal functional tissue by scar tissue or fibrosis. Someof the current antihypertensive agents are able to slow the progressionof the replacement of functional tissue by fibrosis, but none have beenshown to reverse existing fibrosis and restore normal tissuearchitecture. There is thus a need for agents which have the efficacy toreduce BP significantly and thus enable a larger proportion of patientsto attain BP target with single agent therapy and/or to reverse existingfibrosis and/or restore normal tissue architecture.

It is an object of the present invention to overcome or ameliorate atleast one of the disadvantages of the prior art, or to provide a usefulalternative.

SUMMARY OF THE INVENTION

Surprisingly, the present inventors have found that certain compoundshave blood pressure lowering and/or anti-fibrotic effects. These effectsmay be seen in intravenous and/or oral dosing studies.

According to one aspect, the present invention provides a compound ofthe formulae:

wherein:X is selected from the group consisting of:

R₁ to R₉ are independently C, N, O or S;R₁₀ is independently selected from C₁₋₆alkyl, halo, C₀₋₆alkyl carboxylicacid, amino, hydroxy and C₁₋₆alkoxy;Y is A, CH₂-A or CH=A;A is selected from optionally substituted saturated, partly saturated orunsaturated 5- or 6-membered heterocyclyl; optionally substitutedC₁₋₆alkoxyl amine; optionally substituted C₁₋₆alkyl amine; optionallysubstituted C₀₋₆alkyl carboxylic acid; optionally substituted C₁₋₆alkylhydroxyl; optionally substituted saturated or unsaturated C₀₋₆alkylbicyclic heterocyclyl; and optionally substituted saturated orunsaturated C₁₋₆alkoxyl bicyclic heterocyclyl;Z is selected from the group consisting of:

R₁₁ is independently selected from halo, alkyl, hydroxy, amino andsubstituted amino;R₁₂, R₁₄ and R₁₅ are independently C, CH, CH₂, O, N, NH or S;R₁₃ is C, CH, CH₂, N, NH, C—CF₃, CH—CF₃ or C═O;m is 0, 1, 2, 3, 4 or 5; andn is 0, 1, 2, 3 or 4,or a stereoisomer or pharmaceutically acceptable salt thereof.

In one embodiment, R₁₀ is independently selected

from —CH₃, —C(O)OH, —F, —NH₂, —OH and —OCH₃.

In one embodiment, R₅ to R₉ are independently C or N.

In one embodiment, the C₀₋₆alkyl carboxylic acid is carboxylic acid.

In one embodiment, the saturated, partly saturated or unsaturated 5- or6-membered heterocyclyl contains one or more of N, S or O, optionallysubstituted with one or more oxo, C₁₋₆alkyl, amino, hydroxyl or halosubstituents.

In one embodiment, the saturated, partly saturated or unsaturated 5- or6-membered heterocyclyl is selected from pyrrolyl, pyrazolyl,imidazolyl, triazolyl, imidazolidinyl, pyrrolidinyl, pyrrolidinylidene,dihydropyrrolyl, isoxazolyl dihydrooxazolyl, isoxazolidinyl,oxazolidinyl and oxazolyl, optionally substituted with one or more oxo,C₁₋₆alkyl, amino, hydroxyl or halo substituents.

In one embodiment, the C₁₋₆alkoxyl amine is aminooxymethyl.

In one embodiment, the C₁₋₆alkyl amine is optionally substituted withone or more of C₁₋₆alkyl, C₁₋₆halo alkyl, hydroxyl or halo, preferablymono-, di- or tri-substituted halo alkyl, most preferably tri-fluoromethane.

In one embodiment, the C₁₋₆alkyl hydroxyl is methyl hydroxyl orpropan-2-ol.

In one embodiment, the C₀₋₆alkyl bicyclic heterocyclyl is selected fromindolyl, isoindolyl, insolinyl and isoindolinyl, optionally substitutedwith one or more oxo, preferably dioxo.

In one embodiment, the C₁₋₆alkoxyl bicyclic heterocyclyl is selectedindolyl, isoindolyl, insolinyl and isoindolinyl, optionally substitutedwith one or more oxo, and wherein the C₁₋₆alkoxyl is methoxy or ethoxy.

In one embodiment, A is selected from:

In one embodiment, R₁₁ is halo selected from the group consisting of F,Cl, Br and I.

In one embodiment, R₁₁ is substituted amino of the formula —NHR₁₆ andwherein:

R₁₆ is selected from —CN, —SO₂(R₁₇)_(a)R₁₈ and —CO(R₁₇)_(a)R₁₈,

a is 0 or 1,

R₁₇ is selected from —NH— and —O—, and

R₁₈ is selected from —H, —CH₃, —CH₂CH₃, —CH₂OH and —CH₂CH₂OH.

In one embodiment, R₁₁ is substituted amino selected from the groupconsisting of —NHSO₂CH₃, —NHCOH, —NHCONHCH₃, —NHCONHCH₂CH₃, —NHSO₂NHCH₃,—NHSO₂NHCH₂CH₃, —NHCOCH₃, —NHCOOCH₃, —NHCOOCH₂CH₂OH, —NHCONH₂ and —NHCN.

In one embodiment, R₁₁ is alkyl selected from the group consisting ofmethyl, ethyl, propyl, butyl and pentyl.

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from:

According to another aspect, the present invention relates to apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable excipient.

According to another aspect, the present invention relates to a methodfor the therapeutic treatment of hypertension or prehypertension in asubject comprising administering to the subject a compound according tothe present invention.

According to another aspect, the present invention relates to a methodfor the therapeutic treatment of fibrosis in a subject comprisingadministering to the subject a compound according to the presentinvention.

According to another aspect, the present invention relates to a methodfor the prophylactic treatment of fibrosis in a subject comprisingadministering to the subject a compound according to the presentinvention.

According to another aspect, the present invention relates to a methodfor the therapeutic treatment of hypertension and fibrosis in a subjectcomprising administering to the subject a compound according to thepresent invention.

According to another aspect, the present invention relates to a methodfor the therapeutic treatment of prehypertension and fibrosis in asubject comprising administering to the subject a compound according tothe present invention.

According to another aspect, the present invention relates to a compoundof the present invention for use in the therapeutic treatment ofhypertension or prehypertension.

According to another aspect, the present invention relates to a compoundof the present invention for use in the therapeutic treatment offibrosis.

According to another aspect, the present invention relates to a compoundof the present invention for use in the prophylactic treatment offibrosis.

According to another aspect, the present invention relates to a compoundof the present invention for use in the therapeutic treatment ofhypertension and fibrosis.

According to another aspect, the present invention relates to a compoundof the present invention for use in the therapeutic treatment ofprehypertension and fibrosis.

According to another aspect, the present invention relates to use of acompound of the present invention for the manufacture of a medicamentfor the therapeutic treatment of hypertension or prehypertension.

According to another aspect, the present invention relates to use of acompound of the present invention for the manufacture of a medicamentfor the therapeutic treatment of fibrosis.

According to another aspect, the present invention relates to use of acompound of the present invention for the manufacture of a medicamentfor the prophylactic treatment of fibrosis.

According to another aspect, the present invention relates to use of acompound of the present invention for the manufacture of a medicamentfor the therapeutic treatment of hypertension and fibrosis.

According to another aspect, the present invention relates to use of acompound of the present invention for the manufacture of a medicamentfor the therapeutic treatment of prehypertension and fibrosis.

In one embodiment, the fibrosis is myocardial fibrosis.

In one embodiment, the fibrosis is kidney fibrosis.

In one embodiment, the fibrosis is liver fibrosis.

In one embodiment, the fibrosis is lung fibrosis.

Unless the context clearly requires otherwise, throughout thedescription and the claims, the words “comprise”, “comprising”, and thelike are to be construed in an inclusive sense as opposed to anexclusive or exhaustive sense; that is to say, in the sense of“including, but not limited to”.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Synthesis of2-[4-Benzyl-1-(3-hydroxybenzyl)-1H-imidazol-5-yl]acetamide (VB0002).

FIG. 2 : Synthesis of 3-(tert-Butyldimethylsilyloxy)benzylisothiocyanate(compound B).

FIG. 3 : Synthesis of3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]-phenol (VB0003).

FIG. 4 : Synthesis of α-Tosylbenzylisocyanide (compound C).

FIG. 5 Synthesis of 3-(Benzyloxy)benzylamine (compound D).

FIG. 6 : Synthesis of 3,3-Ethylenedioxy-1-butanal (compound E).

FIG. 7 : Synthesis of(S)-3-[1-(3-Hydroxy)phenyl-4-phenylpiperazin-2-yl]propanamide (VB0005).

FIG. 8 : Systolic blood pressure in SHR on a 2.2% salt diet with VB0002(in 20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO)administered intravenously via osmotic minipump for 4 weeks. *p<0.005 vs18 week control.

FIG. 9 : Systolic blood pressure in SHR on a 2.2% salt diet with VB0003(in 5% ethanol) at a dose of 20 pmol/kg/min, VB0005 (in 5% ethanol) at adose of 20 pmol/kg/min or vehicle control (5% ethanol) administered inthe drinking solution for 4 weeks. *p<0.0005 vs 18 week control.

FIG. 10 : Myocardial fibrosis in SHR on a 2.2% salt diet with VB0002 (in20% DMSO) at a dose of 20 pmol/kg/min or vehicle control (20% DMSO)administered intravenously via an osmotic minipump for 4 weeks. *p<0.005vs 18 week control, **p<0.0005 vs 18 week control.

FIG. 11 : Myocardial fibrosis in SHR on a 2.2% salt diet with VB0003 (in5% ethanol) at dosages of 10, 100 and 500 pmol/kg/min or vehicle control(5% ethanol) administered in the drinking solution for 4 weeks. *p<0.005vs 18 week control, **p<0.0005 vs 18 week control, #p<0.01 vs 14 weekcontrol.

FIG. 12 : Myocardial fibrosis in SHR on a 2.2% salt diet with VB0005 (in5% ethanol) at a dosage of 100 pmol/kg/min or vehicle control (5%ethanol) administered in the drinking solution for 4 weeks. *p<0.001 vs18 week control, **p<0.0005 vs 18 week control, #p<0.01 vs 14 weekcontrol.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to certain compounds that show bloodpressure lowering and anti-fibrotic effects in oral dosing studies in anexperimental animal model. With respect to anti-fibrotic activity, thecompounds of the present invention are effective in preventing fibrosis,slowing down progression of established fibrosis and/or reducing thedegree (reversal) of established fibrosis. These are important findingswith respect to the range and severity of conditions which can betreated with the compounds of the present invention.

The compounds of the present invention are represented by the formulae:

wherein:X is selected from the group consisting of:

R₁ to R₉ are independently C, N, O or S;R₁₀ is independently selected from C₁₋₆alkyl, halo, C₀₋₆alkyl carboxylicacid, amino, hydroxy and C₁₋₆alkoxy;Y is A, CH₂-A or CH=A;A is selected from optionally substituted saturated, partly saturated orunsaturated 5- or 6-membered heterocyclyl; optionally substituted C₁₋₆alkoxyl amine; optionally substituted C₁₋₆alkyl amine; optionallysubstituted C₀₋₆alkyl carboxylic acid; optionally substituted C₁₋₆alkylhydroxyl; optionally substituted saturated or unsaturated C₀₋₆alkylbicyclic heterocyclyl; and optionally substituted saturated orunsaturated C₁₋₆alkoxyl bicyclic heterocyclyl;Z is selected from the group consisting of:

R₁₁ is independently selected from halo, alkyl, hydroxy, amino andsubstituted amino;R₁₂, R₁₄ and R₁₅ are independently C, CH, CH₂, O, N, NH or S;R₁₃ is C, CH, CH₂, N, NH, C—CF₃, CH—CF₃ or C═O;m is 0, 1, 2, 3, 4 or 5; andn is 0, 1, 2, 3 or 4,or a stereoisomer or pharmaceutically acceptable salt thereof.

The following compounds are specific, but non-limiting, examples of thecompounds of the present invention:

As used herein, the term “halo” designates —F, —Cl, —Br or —I; the term“hydroxy” means —OH; the term “amino” means —NH₂; and the term“substituted amino” includes —NHW, wherein W is selected from —CN,—SO₂(X)_(a)Y and —CO(X)_(a)Y, a is 0 or 1, X is selected from —NH— and—O—, and Y is selected from —H, —CH₃, —CH₂CH₃, —CH₂OH and —CH₂CH₂OH.

As used herein, the abbreviations Me, Et, Ph, Ms represent methyl,ethyl, phenyl, and methanesulfonyl, respectively. A more comprehensivelist of the abbreviations utilized by organic chemists of ordinary skillin the art appears in the first issue of each volume of the Journal ofOrganic Chemistry; this list is typically presented in a table entitledStandard List of Abbreviations. The abbreviations contained in saidlist, and all abbreviations utilized by organic chemists of ordinaryskill in the art are hereby incorporated by reference.

Compounds of the present invention may exist in particular geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-isomers, (R)- and (S)-enantiomers,diastereomers, (d)-isomers, (I)-isomers, the racemic mixtures thereof,and other mixtures thereof, as falling within the scope of theinvention. All such isomers, as well as mixtures thereof, are intendedto be included in this invention.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivatization with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, diastereomericsalts may be formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means well known in the art, andsubsequent recovery of the pure enantiomers.

In general, the compounds of the present invention may be prepared bythe methods illustrated in the general reaction schemes as, for example,described below, or by modifications thereof, using readily availablestarting materials, reagents and conventional synthesis procedures. Inthese reactions, it is also possible to make use of variants which arein themselves known, but are not mentioned here.

The present invention also contemplates pharmaceutically acceptablesalts of the compounds. The term “pharmaceutically acceptable salt”includes both acid and base addition salts and refers to salts whichretain the biological effectiveness and properties of the free bases oracids, and which are not biologically or otherwise undesirable. Thepharmaceutically acceptable salts are formed with inorganic or organicacids or bases, and can be prepared in situ during the final isolationand purification of the compounds, or by separately reacting a purifiedcompound in its free base or acid form with a suitable organic orinorganic acid or base, and isolating the salt thus formed.

The term “fibrosis” as used in the context of the present inventionincludes, but is not limited to, myocardial fibrosis, kidney fibrosis,liver fibrosis and/or lung fibrosis.

In addition to treatment of established fibrosis, the compounds of thepresent invention may be used prophylactically in subjects at risk ofdeveloping fibrosis. As an example of subjects in the risk category fordeveloping fibrosis are those having hypertension, diabetes,myocarditis, ischaemic heart disease, Conn's Syndrome, pheochromocytoma,genetic predisposition high salt diet and/or receiving drugs used incancer chemotherapy (such as daunorubicin). The term “prophylactic” asused in the context of the present invention is intended inter alia toencompass treatments used to prevent or slow down the development offibrosis in the at risk group. Subjects who may be given prophylactictreatment may already have signs of early heart failure onechocardiography.

The term “hypertension” as used in the context of the present inventionindicates an adult blood pressure of above about 139 mmHg systolicand/or above about 89 mmHg diastolic.

The term “prehypertension” as used in the context of the presentinvention indicates an adult blood pressure in the range about 120-139mmHg systolic and/or about 80-89 mmHg diastolic.

The present invention also contemplates pharmaceutical compositionswhich include the compounds of the present invention, in conjunctionwith acceptable pharmaceutical excipients. The term “pharmaceuticallyacceptable excipient” as used in the context of the present inventionmeans any pharmaceutically acceptable inactive component of thecomposition. As is well known in the art, excipients include diluents,buffers, binders, lubricants, disintegrants, colorants,antioxidants/preservatives, pH-adjusters, etc. The excipients areselected based on the desired physical aspects of the final form: e.g.obtaining a tablet with desired hardness and friability being rapidlydispersible and easily swallowed etc. The desired release rate of theactive substance from the composition after its ingestion also plays arole in the choice of excipients. Pharmaceutical compositions mayinclude any type of dosage form such as tablets, capsules, powders,liquid formulations, delayed or sustained release, patches, snuffs,nasal sprays and the like. The physical form and content of thepharmaceutical compositions contemplated are conventional preparationsthat can be formulated by those skilled in the pharmaceuticalformulation field and are based on well established principles andcompositions described in, for example, Remington: The Science andPractice of Pharmacy, 19th Edition, 1995; British Pharmacopoeia 2000 andsimilar formulation texts and manuals.

For example, where the compounds or compositions are to be administeredorally, they may be formulated as tablets, capsules, granules, powdersor syrups; or for parenteral administration, they may be formulated asinjections (intravenous, intramuscular or subcutaneous), drop infusionpreparations or suppositories. For application by the ophthalmic mucousmembrane route, they may be formulated as eyedrops or eye ointments.These formulations can be prepared by conventional means, and, ifdesired, the active ingredient may be mixed with any conventionaladditive, such as an excipient, a binder, a disintegrating agent, alubricant, a corrigent, a solubilizing agent, a suspension aid, anemulsifying agent or a coating agent.

When the compound(s) of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically acceptable carrier.

The dosage of a compound and frequency of administration that should beused can also be easily determined by the practicing physician in orderto produce the desired response.

Although the dosage will vary depending on the symptoms, age and bodyweight of the patient, the nature and severity of the disorder to betreated or prevented, the route of administration and the form of thedrug, in general, a daily dosage of from 0.0001 mg to 200 mg of thecompound of the present invention may be a suitable effective amount foran adult human patient, and this may be administered in a single dose orin divided doses.

A “patient” or “subject” to be treated by the subject method can meaneither a human or non-human subject.

An “effective amount” of a subject compound, with respect to a method oftreatment, refers to an amount of the therapeutic in a preparationwhich, when applied as part of a desired dosage regimen provides abenefit according to clinically acceptable standards for the treatmentor prophylaxis of a particular disorder.

The present invention will now be described in more detail withreference to specific but non-limiting examples describing specificcompositions and methods of use. It is to be understood, however, thatthe detailed description of specific procedures, compositions andmethods is included solely for the purpose of exemplifying the presentinvention. It should not be understood in any way as a restriction onthe broad description of the inventive concept as set out above.

EXAMPLES Example 1—Synthesis of Compounds

The synthetic route used to prepare2-[4-Benzyl-1-(3-hydroxybenzyl)-1H-imidazol-5-yl]acetamide (VB0002) isshown in FIG. 1 . A condensation reaction between Boc-phenylalanine andmethyl malonate potassium salt promoted by 1,1′-carbonyldiimidazole(CDI) gave the intermediate 4. Removal of the Boc group then providedcompound 5 as a hydrochloride salt. The salt 5 was reacted withisothiocyanate B, and the cyclic thiourea 6 was obtained in low yield.Conversion of cyclic thiourea 6 to imidazole 7 was achieved underoxidative conditions. Treatment of imidazole 7 with aqueous ammoniaafforded VB0002.

Compound B was not commercially available, and was prepared as shown inFIG. 2 . 3-Cyanophenol was initially protected as atert-butyldimethylsilyl ether, and the cyano group subsequently reducedto the corresponding amine, which was reacted with thiophosgene to formcompound B.

The synthetic route used to prepare3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]-phenol (VB0003) isshown in FIG. 3 . Firstly, imidazole 8 was conveniently assembled by athree-component coupling reaction of α-tosylbenzylisocyanide C,benzylamine D and the protected aldehyde E. Both protecting groups weresubsequently removed using a thioanisole-trifluoroacetic acid (TFA)system to give compound 9, which was reduced to afford VB0003.

Compound C was prepared as shown in FIG. 4 . 4-Toluenesulfinic acid,prepared from the corresponding sodium salt, was involved in athree-component reaction with benzaldehyde and formamide to form anintermediate which upon dehydration gave compound C.

Compound D was not commercially available and was prepared as shown inFIG. 5 . This was accomplished by converting 3-(benzyloxy)benzyl alcoholinto the corresponding azide using diphenylphosphoryl azide, andsubsequent reduction to give benzylamine D.

Compound E was not commercially available and was prepared as shown inFIG. 6 . Ethyl acetoacetate was initially protected as an acetal; theester group was then reduced to a primary alcohol, which wassubsequently subjected to a Swern oxidation to form protected aldehydeE.

The synthetic route used to prepare(S)-3-[1-(3-Hydroxy)phenyl-4-phenylpiperazin-2-yl]propanamide (VB0005)is shown in FIG. 7 . In a standard amide bond forming processFmoc-L-glutamic acid 5-tert-butyl ester was reacted with aniline to formthe corresponding amide, which was deprotected withtris(2-aminoethyl)amine (TAEA) to give compound 14. The free amine 14underwent a copper-mediated cross-coupling reaction with3-(benzyloxy)phenylboronic acid to afford the N-arylated product 15.This compound was subsequently reacted with bromoacetyl bromide to formcompound 16, which was transformed into keto-piperazine 17; a selectivereduction of this compound yielded piperazine 18. A subsequent doubledeprotection step employing a thioanisole-TFA system gave compound 19,which was subjected to an aminolysis reaction using aqueous ammonia and1,1′-carbonyldiimidazole (CDI) to afford VB0005.

Methyl 4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate (4). Asuspension of magnesium chloride (6.96 g, 73.0 mmol) and methyl malonatepotassium salt (17.66 g, 113.2 mmol) was stirred in THF (280 mL) at 50°C., under a nitrogen atmosphere for 6 h. To a solution ofN-(tert-butoxycarbonyl)-L-phenylalanine (20.0 g, 75.4 mmol) in THF (200mL) in a separate flask, under nitrogen and at 0° C. was addedportionwise 1,1′-carbonyldiimidazole (18.34 g, 113.1 mmol) and thereaction stirred at ambient temperature for 2 h, then added to thecooled malonate suspension. The reaction mixture was then stirred atroom temperature for 17 h. Most of the THF was removed in vacuo. To theresidue was added saturated potassium hydrogen sulphate (300 mL) andethyl acetate (300 mL). The layers were separated then the aqueous layerwas extracted twice more with ethyl acetate. The combined organic layerswere washed with saturated sodium bicarbonate (2×300 mL) and brine (300mL), dried and concentrated in vacuo to give methyl4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate (22.22 g, 92%) asa pale viscous oil which solidified. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.08(m, 5H), 5.20-4.80 (m, 1H), 4.62-4.48 (m, 1H), 3.69 (s, 3H), 3.52 (d,J=16.0 Hz, 1H), 3.45 (d, J=16.0 Hz, 1H), 3.25-2.88 (m, 2H), 1.39 (s,9H). ¹³C NMR (100 MHz, CDCl₃) δ 201.8, 167.3, 155.2, 136.1, 129.2,128.6, 126.9, 80.1, 60.4, 52.3, 46.5, 36.7, 28.2. EIMS: m/z 321 [M]⁺.HRMS calcd for C₁₇H₂₃NO₅ 321.1576, found 321.1555.

Methyl 4-amino-3-oxo-5-phenylpentanoate hydrochloride (5). Methyl4-(tert-butoxycarbonylamino)-3-oxo-5-phenylpentanoate (22.20 g, 69.2mmol) was stirred for 2 days with ethyl acetate saturated with hydrogenchloride. The resultant solid was collected by filtration, washed withdiethyl ether and dried in the air to give methyl4-amino-3-oxo-5-phenylpentanoate hydrochloride (16.25 g, 92%) as anunstable cream solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (br s, 3H),7.37-7.20 (m, 5H), 4.49 (t, J=6.6 Hz, 1H), 3.83 (d, J=17.1 Hz, 1H), 3.74(d, J=17.1 Hz, 1H), 3.62 (s, 3H), 3.22 (dd, J=14.4, 6.4 Hz, 1H), 3.11(dd, J=14.4, 7.0 Hz, 1H).

Methyl2-{5-benzyl-3-[3-(tert-butyldimethylsilyloxy)benzyl]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl}acetate(6). A mixture of methyl 4-amino-3-oxo-5-phenylpentanoate hydrochloride(7.15 g, 27.9 mmol), 3-(tert-butyldimethylsilyloxy)benzylisothiocyanate(9.34 g, 33.5 mmol), triethylamine (5.8 mL, 41.9 mmol) and pyridinium4-toluenesulfonate (0.70 g, 2.8 mmol) in toluene (100 mL) was heated ata gentle reflux under nitrogen for 5 h. The reaction mixture was cooledto room temperature, then partitioned between water (150 mL) and ethylacetate (150 mL). The layers were separated and the aqueous wasextracted twice more with ethyl acetate. The combined organic layerswere washed with water (2×150 mL), dried and concentrated in vacuo togive a tan oil. The crude material was dissolved in diethyl ether,seeded and left to crystallise for 20 h. Methyl2-{5-benzyl-3-[3-(tert-butyldimethylsilyloxy)benzyl)]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl}acetate(2.14 g, 13%) was collected by filtration as a cream needles; mp154.0-156.0° C. ¹H NMR (400 MHz, CDCl₃) δ 9.68 (br s, 1H), 7.34-7.22 (m,2H), 7.19-7.14 (m, 3H), 6.83-6.71 (m, 3H), 5.32 (s, 2H), 3.79 (s, 2H),3.61 (s, 3H), 3.33 (s, 2H), 0.96 (s, 9H), 0.18 (s, 6H). ¹³C NMR (125MHz, CDCl₃) δ 169.1, 161.5, 156.1, 137.4, 136.3, 129.9, 128.9, 128.6,127.2, 125.8, 119.8, 119.5, 119.4, 118.6, 52.4, 47.9, 30.1, 29.6, 25.7,18.2, −4.4. EIMS: m/z 482 [M]⁺. HRMS calcd for C₂₆H₃₄N₂O₃SSi 482.2054,found 482.2039.

Methyl2-{4-benzyl-1-[3-(tert-butyldimethylsilyloxy)benzyl]-1H-imidazol-5-yl}acetate(7). To a suspension of methyl2-{5-benzyl-3-[3-(tert-butyldimethylsilyloxy)benzyl]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl}acetate(1.00 g, 2.1 mmol) in acetic acid (3.4 mL) under nitrogen, was slowlyadded 30% hydrogen peroxide (941 μL). After 10 min the reaction solutionwas cooled in an ice-bath and then quenched with 10% sodium carbonate(20 mL). The pH was adjusted to 9-10 with 1M sodium hydroxide, thenextracted with ethyl acetate (3×20 mL), dried and concentrated in vacuoto give methyl2-{4-benzyl-1-[3-(tert-butyldimethylsilyloxy)benzyl]-1H-imidazol-5-yl}acetate(0.86 g, 91%) as a tan oil. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, 1H),7.27-7.10 (m, 6H), 6.80-6.74 (m, 1H), 6.69-6.60 (m, 1H), 6.50-6.47 (m,1H), 5.06 (s, 2H), 3.93 (s, 2H), 3.55 (s, 3H), 3.38 (s, 2H), 0.95 (s,9H), 0.14 (s, 6H). ¹³C NMR (50 MHz, CDCl₃) δ 170.0, 156.3, 139.9, 139.6,137.3, 136.2, 130.1, 128.6, 128.4, 126.0, 120.4, 119.8, 118.4, 117.4,52.2, 48.9, 33.5, 29.1, 25.6, 18.0, −4.5. EIMS: m/z 450 [M]⁺. HRMS calcdfor C₂₆H₃₄N₂O₃Si 450.2333, found 450.2323.

2-[4-Benzyl-1-(3-hydroxybenzyl)-1H-imidazol-5-yl]acetamide (VB0002). Toa solution of methyl2-{4-benzyl-1-[3-(tert-butyldimethylsilyloxy)benzyl]-1H-imidazol-5-yl}acetate(0.86 g, 1.9 mmol) in methanol (2 mL) was added 25% aqueous ammoniasolution. The flask was stoppered and the reaction mixture stirred atroom temperature for 3 days. More methanol and diethyl ether were addedand the reaction mixture stirred for 2 h. The fine precipitate wascollected by filtration, washing well with diethyl ether, then air driedto give 2-[4-benzyl-1-(3-hydroxybenzyl)-1H-imidazol-5-yl]acetamide(0.193 g, 32%) as a colourless solid; mp 249° C. (dec.). ¹H NMR (400MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.52 (s, 1H), 7.37 (br s, 1H), 7.24-7.07(m, 5H), 6.95 (br s, 1H), 6.66 (m, 1H), 6.53-6.49 (m, 1H), 6.45-6.43 (m,1H), 5.10 (s, 2H), 3.76 (s, 2H), 3.30 (s, 2H). ¹³C NMR (50 MHz, DMSO-d₆)δ 170.8, 157.7, 141.1, 138.9, 137.9, 136.9, 129.7, 128.5, 127.9, 125.5,112.0, 117.3, 114.5, 113.5, 47.7, 32.8, 29.6. EIMS: m/z 321 [M]⁺. HRMScalcd for C₁₉H₁₉N₃O₂ 321.1477, found 321.1470.

3-(tert-Butyldimethylsilyloxy)benzonitrile. To a stirred solution of3-cyanophenol (10.34 g, 86.8 mmol) and imidazole (14.77 g, 217 mmol) inDMF (100 mL) under nitrogen, and at 0° C. was added portionwisetert-butyldimethylsilylchloride (13.74 g, 91 mmol) over 5 min. Thereaction was allowed to warm to ambient temperature and was stirred foranother 2 h. The reaction mixture was transferred to a separatory funneland was partitioned between diethyl ether (150 mL) and water (150 mL).The layers were separated and the aqueous was extracted twice more withdiethyl ether. The combined organic extracts were washed with water(2×100 mL), dried and concentrated to give3-(tert-butyldimethylsilyloxy)benzonitrile (20.38 g, quantitative) as apale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.29 (m, 1H), 7.27-7.22(m, 1H), 7.11-7.04 (m, 2H), 0.98 (s, 9H), 0.21 (s, 6H). ¹³C NMR (100MHz, CDCl₃) δ 156.0, 130.4, 125.0, 124.9, 123.3, 118.5, 113.2, 25.5,18.1, −4.6. EIMS: m/z 233 [M]⁺. HRMS calcd for C₁₃H₁₉NOSi 233.1236,found 233.1227.

3-(tert-Butyldimethylsilyloxy)benzylamine. A mixture of lithiumaluminium hydride (4.97 g, 131 mmol) and diethyl ether (400 mL) washeated at reflux for 1 h, then cooled to ambient temperature. A solutionof 3-(tert-butyldimethylsilyloxy)benzonitrile (15.25 g, 65.5 mmol) indiethyl ether (50 mL) was added dropwise so that a gentle reflux wasmaintained. The reaction was then heated at reflux for 3 h and thencooled in an ice bath. Water (5 mL) was cautiously added dropwise,followed by 15% sodium hydroxide solution (5 mL) and then water (15 mL).The solids were filtered off and washed thoroughly with diethyl ether.The filtrate was washed with water, dried and concentrated in vacuo togive a pale yellow oil (14.68 g, 95%). The crude material waspreadsorbed onto Celite, then chromatographed by DCVC eluting with agradient of ethyl acetate in PE (5%-100% ethyl acetate) to give3-(tert-butyldimethylsilyloxy)benzylamine (11.85 g, 77%) as a paleyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.13 (t, J=7.7 Hz, 1H), 6.84 (d,J=7.7 Hz, 1H), 6.79-6-75 (m, 1H), 6.68 (dd, J=8.0, 2.4 Hz, 1H), 3.75 (s,2H), 0.97 (s, 9H), 0.18 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 155.5,144.7, 129.1, 119.7, 118.5, 118.0, 46.0, 25.4, 17.9, −4.7. EIMS: m/z 237[M]⁺. HRMS calcd for C₁₃H₂₃NOSi 237.1543, found 237.1545.

3-(tert-Butyldimethylsilyloxy)benzylisothiocyanate (B). A mixture of3-(tert-butyldimethylsilyloxy)benzylamine (13.0 g, 54.8 mmol), calciumcarbonate (5.65 g, 56.4 mmol), thiophosgene (8.5 mL, 111 mmol), water(41 mL) and chloroform (356 mL) was stirred vigorously at roomtemperature for 20 h in a stoppered flask. The reaction mixture waswashed with water (2×250 mL), dried and concentrated in vacuo to give3-(tert-butyldimethylsilyloxy)benzylisothiocyanate (14.29 g, 93%) as apale tan oil. ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.21 (m, 1H), 6.92-6.88 (m,1H), 6.83-6.79 (m, 2H), 4.65 (s, 2H), 1.00 (s, 9H), 0.22 (s, 6H). ¹³CNMR (100 MHz, CDCl₃) δ 156.1, 135.7, 132.4, 129.9, 120.0, 119.6, 118.5,48.4, 25.6, 18.2, −4.4. EIMS: m/z 279 [M]⁺. HRMS calcd for C₁₄H₂₁NOSi279.1108, found 279.1105.

1-(3-Benzyloxybenzyl)-5-(2-methyl-1,3-dioxolan-2-yl-methyl)-4-phenyl-1H-imidazole(8). To a solution of 3,3-ethylenedioxy-1-butanal (1.37 g, 10.5 mmol) indry methanol (60 mL) was added 3-benzyloxybenzyl amine (2.10 g, 10.5mmol) and the clear solution was allowed to stir at 25° C. for 90 min.α-Tosylbenzylisocyanide (2.86 g, 10.5 mmol) was added, followed bytriethylamine (2.93 mL, 21.1 mmol), and the reaction mixture was stirredand heated at 65° C. for 4 h. The solvent was then removed and theresidue dissolved in ethyl acetate (50 mL), washed with water (50 mL),dried and the solvent removed in vacuo. The residue was purified bycolumn chromatography (gradient elution using 20-80% ethyl acetate/PE)to afford1-(3-benzyloxybenzyl)-5-(2-methyl-[1,3]-dioxalan-2-yl-methyl)-4-phenyl-1H-imidazole(2.05 g, 44%) as a sticky pale orange oil. ¹H NMR (200 MHz, CDCl₃) δ7.89 (m, 2H) 7.58 (s, 1H), 7.21-7.7.44 (m, 9H), 6.90 (m, 1H), 6.65 (m,2H), 5.31 (s, 2H), 5.01 (s, 2H), 3.83 (m, 2H), 3.59 (m, 2H), 3.02 (s,2H), 1.33 (s, 3H). ¹³C NMR (50 MHz, CDCl₃) δ 159.2, 138.5, 137.6, 136.6,135.3, 130.0, 128.6, 128.3, 128.0, 127.4, 127.2, 126.5, 119.0, 114.0,113.1, 109.9, 69.9, 65.0, 48.8, 33.9, 29.7, 25.5. ESIMS: m/z 441 [M+H]⁺.HRMS calcd for C₂₈H₂₈N₂O₃ 440.2094, found 440.2075.

1-[3-(3-hydroxybenzyl)-5-phenyl-3H-imidazol-4-yl]-propan-2-one (9). To astirred solution of1-(3-benzyloxybenzyl)-5-(2-methyl-[1,3]-dioxolan-2-yl-methyl)-4-phenyl-1H-imidazole(1.12 g, 2.54 mmol) in TFA (5 mL) was added thioanisole (598 μL, 5.09mmol) and the reaction allowed to stir at 25° C. for 15 h. The reactionmixture was then cooled to 0° C., and water (30 mL) was slowly addedfollowed by ethyl acetate (50 mL). The mixture was transferred to aseparatory funnel and the aqueous layer removed. The organic phase waswashed with water (2×50 mL), dried and the solvent removed in vacuo. Theresidue was then passed through a small plug of silica gel (90% ethylacetate/PE), the solvent removed under reduced pressure, andrecrystallised from chloroform/PE to give1-[3-(3-hydroxybenzyl)-5-phenyl-3H-imidazol-4-yl]propan-2-one (419 mg,54%) as a white solid; mp 173.7-175.5° C. ¹H NMR (200 MHz, CD₃CN) δ 8.52(s, 1H), 7.48 (s, 5H), 7.25 (t, 1H, J=7.8 Hz), 6.79 (m, 3H), 5.16 (s,2H), 3.94 (s, 2H), 2.14 (s, 3H). ¹³C NMR (50 MHz, CD₃OD) δ 204.6, 159.6,136.7, 136.0, 134.5, 131.7, 131.1, 130.5, 129.2, 128.3, 126.0, 120.0,117.1, 116.0, 52.1, 38.7, 29.5. ESIMS: m/z 307 [M+H]⁺. HRMS calcd forC₁₉H₁₈N₂O₂ 306.1363, found 306.1365.

3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]-phenol (VB0003). Toan ice-cold solution of1-[3-(3-Hydroxybenzyl)-5-phenyl-3H-imidazol-4-yl]propan-2-one (419 mg,1.37 mmol) in dry methanol (50 mL) was added sodium borohydride (155 mg,4.10 mmol) and the mixture allowed to stir at 25° C. for 15 h. Acetone(20 mL) was then added and the reaction mixture was stirred for afurther 2 h. The solvent was then removed in vacuo; the residue wasdissolved in ethyl acetate (50 mL), washed with water (50 mL) and theorganic phase dried and the solvent removed under reduced pressure. Theresulting solid was recrystallised from methanol, collected and washedwith cold acetonitrile (4×) to afford3-[5-(2-hydroxpropyl)-4-phenyl-imidazol-1-ylmethyl]-phenol (210 mg, 50%)as a white solid; mp 193-194° C. ¹H NMR (200 MHz, CD₃OD) δ 7.72 (s, 1H),7.62 (m, 2H), 7.39 (m, 2H), 7.28 (d, 1H, J=7.4 Hz), 7.18 (m, 1H), 6.72(m, 1H), 6.65 (d, 2H, J=7.6 Hz), 6.54 (s, 1H), 5.34 (d, 1H, J=16.0 Hz),5.24 (d, 1H, J=16.0 Hz), 3.90 (sextet, 1H), 2.82 (d, 2H, J=6.4 Hz), 1.05(d, 3H, J=6.2 Hz). ¹³C NMR (50 MHz, CD₃OD) δ 159.3, 140.2, 139.8, 138.7,136.4, 131.1, 129.5, 128.7, 127.9, 127.4, 118.9, 115.9, 114.6, 68.4,34.1, 23.3. ESIMS: m/z 309 [M+H]⁺. HRMS calcd for C₁₉H₂₀N₂O₂ 308.1519,found 308.1517. HPLC purity=98%.

4-Toluenesulfinic acid. A 500 mL Erlenmeyer flask was charged with4-toluenesulfinic acid sodium salt tetrahydrate (26.82 g, 0.11 mol) andwater (134 mL) and stirred for 30 min until all the solid dissolved.tert-Butylmethyl ether (134 mL) was added to the stirred solutionfollowed by the slow addition of 32% HCl (12.2 mL, 0.11 mol) over 5 min.The reaction was stirred for 30 min and transferred to a separatoryfunnel, and the organic phase separated and diluted with toluene (134mL). The solvent was concentrated to ca. 50 mL on a rotary evaporator,after which heptane (40 mL) was added to give a solid that was collectedusing a Büchner funnel. Subsequent washing with heptane (50 mL) anddrying under vacuum gave 4-toluenesulfinic acid (15.48 g, 93%) as awhite solid.

N-(α-Tosylbenzyl)formamide. A 500 mL, three-necked, flask fitted with areflux condenser was charged with acetonitrile (35 mL), toluene (35 mL),benzaldehyde (6.74 mL, 66 mmol), formamide (6.57 mL, 166 mmol) and TMSCl(9.18 mL, 72 mmol). After heating the reaction mixture for 4 h at 50° C.(internal temperature), 4-toluenesulfinic acid (15.48 g, 99 mmol) wasadded with stirring. Within 1 h a solid had formed and the reaction wasstirred with a teflon stirring rod every 30 min for a period of 4 h. Thereaction was then allowed to cool to room temperature, andtert-butylmethyl ether (35 mL) was added and the stirring continued for5 min after which water (170 mL) was added. The solid was collected on aBüchner funnel, washed with tert-butylmethyl ether (2×50 mL) and driedin vacuo to give N-(α-tosylbenzyl)formamide (16.73 g, 82%). ¹H NMR (200MHz, DMSO-d₆) δ 9.77 (d, 1H, J=10.6 Hz) 7.96 (s, 1H), 7.71 (d, 2H, J=8.2Hz), 7.54 (m, 2H), 7.42 (m, 5H), 6.38 (d, 1H, J=10.6 Hz), 2.41 (s, 3H).

α-Tosylbenzylisocyanide (C). A 500 mL, three-necked, flask fitted with athermometer was charged with N-(α-tosylbenzyl)formamide (16.73 g, 57.8mmol) and dry THF (120 mL). Phosphorus oxychloride (10.78 mL, 116.0mmol) was added via syringe and resulting solution allowed to stir for 5min at 25° C. After cooling the solution to ca. 0° C. with an ice/saltbath, triethylamine (48.4 mL, 347.0 mmol) was added by means of adropping funnel over 45 min whilst keeping the internal temperaturebelow 10° C. After the triethylamine addition was complete, the reactionwas stirred for 45 min at 5-10° C. (ice bath). Ethyl acetate (85 mL)then water (85 mL) was added to the reaction, the mixture stirred for 5min and, after transferring the mixture to a separatory funnel, theaqueous layer removed. The organic phase was washed with water (2×85mL), saturated sodium bicarbonate solution (85 mL), brine (50 mL) andconcentrated under reduced pressure until a slurry remained. The residuewas diluted with n-propanol (85 mL) and concentrated to half itsoriginal volume. The precipitate was cooled to 0° C. for 15 min,collected on a Büchner funnel, washed with n-propanol (2×50 mL) anddried in vacuo. This afforded α-tosylbenzylisocyanide (7.47 g, 48%) as abeige solid. ¹H NMR (200 MHz, CDCl₃) δ 7.60 (d, 2H, J=8.2 Hz) 7.30-7.52(m, 7H), 5.61 (s, 1H), 2.47 (s, 3H).

3-(Benzyloxy)benzyl azide. To a stirred solution of 3-benzyloxybenzylalcohol (5.0 g, 23.3 mmol) and diphenylphosphoryl azide (6.03 mL, 28.0mmol) in dry toluene (40 mL) at 0° C., under an argon atmosphere, wasadded 1,8-diazabicyclo[5.4.0]undec-7-ene (3.83 mL, 25.6 mmol). Theresulting mixture was allowed to warm to ambient temperature, andstirred for 18 h. The reaction mixture was washed with water (2×) and 5%HCl solution (1×), then dried and concentrated under reduced pressure.The crude material was filtered through a short column of silica,eluting with 4/96 ethyl acetate/pentane, to afford 3-(benzyloxy)benzylazide (5.28 g, 95%) as a clear colourless oil. ¹H NMR (200 MHz, CDCl₃) δ7.48-7.22 (m, 6H); 6.99-6.86 (m, 3H); 5.07 (s, 2H); 4.30 (s, 2H). ¹³CNMR (50 MHz, CDCl₃) δ 159.4, 137.2, 137.0, 130.1, 128.8, 128.3, 127.7,120.9, 114.9, 114.9, 70.3, 54.9. u_(N,N,N)/cm⁻¹ 2101.

3-(Benzyloxy)benzylamine(D). 3-(Benzyloxy)benzyl azide (1.0 g, 4.2 mmol)was dissolved in anhydrous THF (20 mL) and the solution cooled to −70°C. Solid lithium aluminium hydride (238 mg, 6.3 mmol) in THF (6 mL) wasadded dropwise under an argon atmosphere. After the addition, thereaction was allowed to warm to 0° C. and stirred for 1 h. The reactionwas carefully quenched with water, then 1.0 M Rochelle's salt was addedand extracted with diethyl ether (3×). The combined organic extractswere washed with brine (1×) then dried and concentrated to afford3-(benzyloxy)benzylamine (787 mg, 88%) as a clear, pale yellow oil.Further purification was not required. ¹H NMR (200 MHz, CDCl₃) δ7.48-7.17 (m, 6H); 6.98-6.79 (m, 3H); 5.06 (s, 2H); 3.83 (s, 2H), 1.43(br s, 2H).

Ethyl 3,3-ethylenedioxybutanoate. A mixture of ethyl acetoacetate (9.72mL, 76.84 mmol), ethylene glycol (7.50 mL, 134.50 mmol) andp-toluenesulfonic acid (15 mg, 0.08 mmol) in benzene (125 mL) was heatedat reflux under Dean-Stark conditions for 24 h. The reaction mixture wasallowed to cool, then washed with 5% NaHCO₃ solution (1×) and water(2×), dried and concentrated to afford ethyl 3,3-ethylenedioxy-butanoate(11.67 g, 87%) as a clear, colourless oil. Further purification was notrequired. ¹H NMR (200 MHz, CDCl₃) δ 4.16 (q, 2H, J=7.2 Hz); 3.97 (s,4H); 2.66 (s, 2H); 1.50 (s, 3H); 1.26 (t, 3H, J=7.2 Hz). ¹³C NMR (100MHz, CDCl₃) δ 169.7, 107.9, 65.0, 60.8, 44.5, 24.7, 14.4. u_(C═O)/cm⁻¹1741.

3,3-Ethylenedioxy-1-butanol. A solution of ethyl3,3-ethylenedioxybutanoate (5.0 g, 28.70 mmol) in anhydrous THF (10 mL)was added dropwise under an argon atmosphere, to a suspension of lithiumaluminium hydride (1.10 g, 28.70 mmol) in THF (50 mL) at −10° C. Thereaction was stirred at 0° C. for 1.5 h, and then quenched with a 1.0 Msolution of Rochelle's salt (75 mL). The mixture was extracted withdiethyl ether (3×), then the combined organic extracts washed with brine(1×) then dried and concentrated to afford 3,3-ethylenedioxy-1-butanol(3.43 g, 90%) as a clear, pale yellow liquid. Further purification wasnot required. ¹H NMR (200 MHz, CDCl₃) δ 3.99 (s, 4H), 3.76 (q, 2H, J=5.6Hz), 2.78 (t, 1H, J=5.6 Hz), 1.95 (m, 2H), 1.36 (s, 3H).

3,3-Ethylenedioxy-1-butanal (E). Into a dropping funnel was added dryDMSO (4.42 mL, 62.3 mmol) and dry dichloromethane (25 mL). This solutionwas added dropwise over a period of 10 min to a stirred solution ofoxalyl chloride (2.64 mL, 31.14 mmol) in dry dichloromethane (75 mL) at−78° C. After 10 min, a solution of2-(2-methyl-1,3-dioxolan-2-yl)ethanol (3.43 g, 26.0 mmol) in drydichloromethane (25 mL) was added dropwise (by means of a droppingfunnel) over a period of 10 min. The resultant solution was stirred at−78° C. for 15 min, and then triethylamine (14.47 mL, 103.8 mmol) wasadded dropwise via syringe. The cooling bath was removed and thereaction mixture allowed to stir for a further 30 min. Water (70 mL) wasthen added, and stirring continued for a further 10 min. The organicphase was separated, and the aqueous phase washed with dichloromethane(70 mL). The combined organics were washed with water (4×70 mL), driedand the solvent removed in vacuo. The residue was purified by filtrationthrough a small plug of silica gel (dichloromethane) to give2-(2-methyl-[1,3]-dioxolan-2-yl)acetaldehyde (1.40 g, 42%) as a paleyellow oil. ¹H NMR (200 MHz, CDCl₃) δ 9.75 (t, 1H, J=2.8 Hz), 4.04-3.98(m, 4H), 2.71 (d, 2H, J=2.8 Hz), 1.43 (s, 3H).

(S)-tert-Butyl-(4-amino-5-oxo-5-phenylamino)pentanoate (14). To astirred solution of(S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoicacid (25.3 g, 57 mmol) in DMF (150 mL) was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (12.08 g, 63 mmol),1-hydroxybenzotriazole hydrate (8.51 g, 63 mmol) and aniline (5.2 mL, 57mmol), and the reaction mixture allowed to stir at ambient temperaturefor 2 days. Water (300 mL) was added followed by ethyl acetate (300 mL).The mixture was transferred to a separatory funnel and the layersseparated. The aqueous layer was extracted twice more with ethylacetate. The combined organic layers were washed with water (2×300 mL),dried and the solvent removed in vacuo to give crude(S)-tert-butyl-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(phenylamino)pentanoateas a yellow oil. It was used without purification in the next step. To astirred solution of crude(S)-tert-butyl-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(phenylamino)pentanoatein dichloromethane (300 mL) was added tris(2-aminoethyl)amine (40 mL,267 mmol) and the reaction mixture stirred at ambient temperature for1-2 h. The reaction mixture was then washed with pH 5.5 phosphate buffer(2×200 mL), then water (200 mL), dried and the solvent removed in vacuo.The residue was dissolved in dichloromethane and an insoluble by-productwas removed by filtration. The solution was preadsorbed onto Celite,then chromatographed (DCVC) eluting with gradient of chloroform in PE,and then a gradient of ethyl acetate in chloroform. Like fractions werecombined to give (S)-tert-butyl-(4-amino-5-oxo-5-phenylamino)pentanoate(10.85 g, 68%) as pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 9.41 (br s,1H), 7.63-7.55 (m, 2H), 7.37-7.28 (m, 2H), 7.12-7.07 (m, 1H), 3.51 (dd,J=7.6, 5.0 Hz, 1H), 2.49-2.34 (m, 2H), 2.26-2.15 (m, 1H), 1.96-1.84 (m,1H), 1.66 (br s, 2H), 1.45 (s, 9H). ¹³C NMR (50 MHz, CDCl₃) δ 172.8,172.6, 137.7, 129.0, 124.1, 119.4, 80.8, 55.2, 32.2, 30.2, 28.1. EIMS:m/z 278 [M]⁺. HRMS calcd for C₁₃H₂₂N₂O₃ 278.1625, found 278.1612.

(S)-tert-butyl4-[(3-benyloxy)phenylamino]-5-oxo-5-(phenylamino)pentanoate (15). Asolution of 3-(benzyloxy)phenylboronic acid (7.05 g, 30.0 mmol) intoluene (150 mL) was azeotropically refluxed for 2.5 h, under nitrogen,to form 2,4,6-tris(3-benzyloxy)phenyl)-1,3,5,2,4,6-trioxatriborinane.Toluene was removed in vacuo and to the residue, at ambient temperature,was added a solution of(S)-tert-butyl-(4-amino-5-oxo-5-phenylamino)pentanoate (4.30 g, 15.5mmol) in dichloromethane (100 mL), pyridine (2.5 mL, 30.9 mmol) andanhydrous copper(II) acetate (4.64 g, 23.2 mmol). The reaction mixturewas opened to the air and allowed to stir at ambient temperature for 2days. The reaction mixture was then poured onto a short column packedwith silica gel and topped with a layer of Celite. The crude product waseluted with chloroform and fractions containing the crude product werecombined. The crude material was preadsorbed onto Celite and thenpurified by silica gel DCVC eluting with a gradient of chloroform in PE(60-100% chloroform) to give (S)-tert-butyl4-[(3-benyloxy)phenylamino]-5-oxo-5-(phenylamino)pentanoate (3.35 g,50%) as a pale tan oil. ¹H NMR (400 MHz, CDCl₃) δ 8.69 (br s, 1H),7.57-7.48 (m, 2H), 7.46-7.23 (m, 7H), 7.15-7.06 (m, 2H), 6.49-6.42 (m,1H), 6.33-6.24 (m, 2H), 5.06-5.02 (m, 1H), 5.00 (s, 2H), 3.80-3.72 (m,1H), 2.67-2.54 (m, 1H), 2.49-2.37 (m, 1H), 2.36-2.24 (m, 1H), 2.21-2.09(m, 1H), 1.46 (s, 9H). ¹³C NMR (50 MHz, CDCl₃) δ 173.6, 171.3, 160.0,148.2, 137.3, 136.9, 130.2, 128.9, 128.5, 127.8, 127.4, 124.4, 119.9,106.8, 105.5, 100.8, 81.3, 69.8, 61.1, 32.7, 28.0, 27.8. EIMS: m/z 460[M]⁺. HRMS calcd for C₂₈H₃₂N₂O₄ 460.2357, found 460.2341.

(S)-tert-butyl4-[N-(3-benzyloxy)phenyl-2-bromoacetamido]-5-oxo-5-(phenylamino)pentanoate(16). To a stirred solution of (S)-tert-butyl4-(3-benyloxyphenylamino)-5-oxo-5-(phenylamino)pentanoate (4.05 g, 8.80mmol) in dichloromethane (80 mL), under nitrogen and at −30° C. wasadded sequentially triethylamine (1.22 mL, 8.80 mmol),N,N-dimethylaminopyridine (20 mg) and bromoacetyl bromide (941 μL, 10.80mmol). The reaction mixture was allowed to warm up to ambienttemperature and then stirred for 30 min. The reaction mixture wastransferred to a separatory funnel, washed with 10% citric acid (50 mL)and brine (2×50 mL), dried and the solvent removed in vacuo. The residuewas preadsorbed onto Celite, then purified by silica gel DCVC to(S)-tert-butyl4-[N-(3-benzyloxy)phenyl-2-bromoacetamido]-5-oxo-5-(phenylamino)pentanoate(4.28 g, 83%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.61 (brs, 1H), 7.63-7.53 (m, 2H), 7.49-7.21 (m, 8H), 7.17-7.09 (m, 1H),7.08-7.02 (1H), 6.89-6.84 (m, 2H), 5.21 (dd, J=8.8, 6.2 Hz, 1H), 5.04(br s, 2H), 3.64 (dd, J=19.7, 11.2 Hz, 2H), 2.44-2.19 (m, 2H), 2.05-1.91(m, 1H), 1.80-1.67 (m, 1H), 1.43 (s, 9H). ¹³C NMR (50 MHz, CDCl₃) δ171.8, 168.2, 167.8, 159.4, 138.3, 137.8, 136.1, 130.4, 128.9, 128.5,128.1, 127.5, 124.3, 121.4, 119.9, 116.6, 115.5, 80.7, 70.2, 59.4, 31.8,28.0, 27.4, 23.9. EIMS: m/z 581 [M]⁺. HRMS calcd for C₃₀H₃₃BrN₂O₅580.1567, found 580.1547.

(S)-tert-Butyl3-[1-(3-benzyloxy)phenyl-3,6-dioxo-4-phenylpiperazine-2-yl]propanoate(17). To a stirred solution of (S)-tert-butyl4-[N-(3-benzyloxy)phenyl-2-bromoacetamido]-5-oxo-5-(phenylamino)pentanoate(4.15 g, 7.15 mmol) in DMF (70 mL), under nitrogen and cooled in anice-bath, was added cesium carbonate (2.33 g, 7.15 mmol). The reactionmixture was allowed to warm up to ambient temperature and was stirredfor 4 h. The mixture was cooled in an ice-bath and water (100 mL) wasadded followed by ethyl acetate (100 mL). The mixture was transferred toa separatory funnel and the layers separated. The aqueous phase wasextracted twice more with ethyl acetate. The combined organic layerswere washed with 10% citric acid (100 mL), saturated sodium bicarbonate(100 mL) and brine (100 mL), dried and the solvent removed in vacuo. Theresidue was preadsorbed onto Celite then purified by silica gel DCVC.Like fractions were combined, then triturated with diethyl ether to give(S)-tert-butyl3-[1-(3-benzyloxy)phenyl-3,6-dioxo-4-phenylpiperazine-2-yl]propanoate(4.18 g, 59%) as a colourless solid; mp 141.6-143.6° C. ¹H NMR (400 MHz,CDCl₃) δ 7.48-7.29 (m, 11H), 7.03-6.95 (m, 3H), 5.08 (s, 2H), 4.55 (dd,J=17.6, 17.0 Hz, 2H), 4.45 (dd, J=9.1, 5.2 Hz, 1H), 2.52-2.14 (m, 4H),1.37 (s, 9H). ¹³C NMR (50 MHz, CDCl₃) δ 171.4, 165.7, 163.8, 159.6,139.9, 139.8, 136.5, 130.4, 129.3, 128.6, 128.1, 127.6, 127.4, 125.1,119.3, 114.7, 113.7, 81.0, 70.25, 63.9, 52.9, 30.6, 28.0, 26.9. EIMS:m/z 500 [M]⁺. HRMS calcd for C₃₁H₃₂N₂O₃ 500.2306, found 500.2294.

(S)-tert-Butyl3-[1-(3-benzyloxy)phenyl-4-phenylpiperazine-2-yl]propanoate (18). To astirred solution of (S)-tert-butyl3-[1-(3-benzyloxy)phenyl-3,6-dioxo-4-phenylpiperazine-2-yl]propanoate(2.97 g, 5.95 mmol) in anhydrous THF (40 mL) under nitrogen, was addedborane-methylsulfide complex (7.14 mL, 14.30 mmol, 2M in THF) and thereaction allowed to stir at ambient temperature for 20 h. The reactionmixture was then cooled in an ice-bath and a solution of methanol (2 mL)in THF (8 mL) was added dropwise. The solvent was removed in vacuo,whereupon more methanol (10 mL) was added. The solvent was removed invacuo and this procedure was repeated once more. The residue waspreadsorbed onto Celite then purified by silica gel (DCVC) eluting witha gradient of ethyl acetate in PE (2%-7% ethyl acetate) to give(S)-tert-butyl3-[1-(3-benzyloxy)phenyl-4-phenylpiperazine-2-yl]propanoate (2.08 g,74%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.42 (m, 2H),7.42-7.35 (m, 2H), 7.35-7.25 (m, 3H), 7.19-7.13 (m, 1H), 6.97-6.92 (m,2H), 6.91-6.85 (m, 1H), 6.57-6.52 (m, 2H), 6.48-6.42 (m, 1H), 5.06 (s,2H), 3.97-3.88 (m, 1H), 3.61-3.50 (m, 2H), 3.50-3.41 (m, 1H), 3.38-3.27(m, 1H), 3.13-3.04 (m, 1H), 3.03-2.29 (m, 1H), 2.33-2.14 (m, 2H),2.12-1.90 (m, 2H), 1.41 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 172.6,160.1, 151.7, 151.2, 137.3, 13.0, 129.2, 128.5, 127.9, 127.6, 119.9,116.4, 108.8, 104.5, 103.2, 80.4, 70.0, 55.2, 51.8, 48.8, 43.1, 32.7,28.1, 22.8. EIMS: m/z 472 [M]⁺. HRMS calcd for C₃₀H₃₆N₂O₃ 472.2720,found 472.2710.

(S)-3-[1-(3-Hydroxy)phenyl-4-phenylpiperazin-2-yl]propanoic acid (19).To a stirred solution of (S)-tert-butyl3-[1-(3-benzyloxy)phenyl-4-phenylpiperazine-2-yl]propanoate (0.82 g,1.75 mmol) in trifluoroacetic acid (3.5 mL) was added thioanisole (620μL, 5.22 mmol) and the reaction allowed to stir at ambient temperaturefor 3 days. The reaction mixture was then cooled to 0° C., and water (10mL) was slowly added followed by EtOAc (15 mL). The mixture wastransferred to a separatory funnel, the layers separated and the aqueousphase extracted twice more with EtOAc, dried and the solvent removed invacuo. The dark tan oil was predsorbed onto Celite, then chromatographed(DCVC) eluting with a gradient of methanol in chloroform (0-5% MeOH) togive (S)-3-[1-(3-hydroxy)phenyl-4-phenylpiperazin-2-yl]propanoic acid(418 mg, 70%) as a tan foam. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m,2H), 7.30-7.24 (m, 2H), 7.17 (br s, 1H), 7.08-7.00 (m, 3H), 6.92-6.79(m, 2H), 3.99-3.89 (m, 1H), 3.70-3.37 (m, 6H), 2.42-2.18 (m, 2H),2.02-1.88 (m, 2H). ¹³C NMR (50 MHz, MeOH-d₄) δ 175.8, 160.6, 151.0,144.0, 132.6, 130.6, 123.0, 118.5, 116.7, 112.7, 109.3, 63.7, 55.6,53.7, 49.2, 30.8, 25.0. EIMS: m/z 326 [M]⁺. HRMS calcd for C₁₉H₂₂N₂O₃326.1625, found 326.1620.

(S)-3-[1-(3-Benzyloxy)phenyl-4-phenylpiperazin-2-yl]propanoic acid (230mg, 30%) was also obtained from this reaction and was isolated as a paletan foam. ¹H NMR (400 MHz, CDCl₃) δ 10.59 (br s, 1H), 7.45-7.25 (m, 8H),7.17-6.90 (m, 6H), 5.07 (s, 2H), 3.99-3.88 (m, 1H), 3.76-3.41 (m, 6H),2.33-2.15 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 176.2 160.1, 148.9, 144.3,136.2, 131.1, 129.6, 128.7, 128.2, 127.6, 122.8, 117.8, 113.5, 112.6,107.5, 70.3, 60.5, 52.7, 52.4, 48.9, 29.9, 23.3. EIMS: m/z 416 [M]⁺.HRMS calcd for C₂₆H₂₈N₂O₃ 416.2094, found 416.2091.

(S)-3-[1-(3-Hydroxy)phenyl-4-phenylpiperazin-2-yl]propanamide (VB0005).

To a stirred solution of(S)-3-[1-(3-hydroxy)phenyl-4-phenylpiperazin-2-yl]propanoic acid (0.76g, 2.32 mmol) in THF (20 mL) was added 1,1′-carbonyldimidazole (0.94 g,5.80 mmol) and the reaction stirred for 2 h. Aqueous ammonia solution(25%) (20 mL) was added and the reaction stirred for a further 3 h. Thereaction mixture was transferred to a separatory funnel and the layersseparated. The aqueous phase was then extracted with ethyl acetate (2×20mL). Combined organic layers were washed with brine (20 mL), dried andconcentrated in vacuo. The crude residue was passed through a shortflorsil column eluting with a gradient of EtOAc in PE (50-100% ethylacetate). Like fractions were combined, dissolved in dichloromethane (20mL) and washed with water (3×20 mL). A solid crystallised out from thewet dichloromethane. Petroleum ether 40-60° C. was added and the mixtureleft for 1 h. The resultant solid was collected by filtration to giveracemic product (100 mg, 13%). The filtrate was concentrated to drynessto give (S)-3-[1-(3-hydroxy)phenyl-4-phenylpiperazin-2-yl]propanamide(185 mg, 21%) as a pale tan foam. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.24(m, 2H), 7.13-7.06 (m, 1H), 6.95-6.84 (m, 4H), 6.47-6.41 (m, 2H),6.35-6.30 (m, 1H), 5.74 (br s, 1H), 5.53 (br s, 1H), 4.00-3.91 (m, 1H),3.60-3.41 (m, 3H), 3.35-3.23 (m, 1H), 3.10-3.00 (m, 1H), 3.00-2.90 (m,2H), 2.32-1.96 (m, 4H). ¹³C NMR (50 MHz, CDCl₃) δ 176.0, 157.3, 151.6,151.2, 130.4, 129.2, 119.9, 116.4, 107.5, 106.3, 102.9, 54.7, 51.7,48.8, 42.9, 32.7, 23.4. EIMS: m/z 325 [M]⁺. HRMS calcd for C₁₉H₂₃N₃O₂325.1790, found 325.1776. [α]_(D)=−13.5° (CHCl₃, c=0.005).

3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]phenol hydrochloride(20). A solution of3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]phenol (14 mg, 0.05mmol), concentrated hydrochloric acid (3.6 μL, 0.05 mmol) and methanol(1 mL) was allowed to stir at ambient temperature for 20 min. Thesolvent was then removed in vacuo; the residue was then taken up indiethyl ether (2 mL), the solvent removed under reduced pressure and theprocedure repeated. The resulting white foam was dried in vacuo at 35°C., dissolved in water (10 mL), filtered through a plug of glass filterpaper and freeze-dried to afford3-[5-(2-hydroxypropyl)-4-phenyl-imidazol-1-ylmethyl]phenol hydrochlorideas a fluffy white solid; mp 84-88° C. ¹H NMR (400 MHz, CD₃OD) δ 8.84 (s,1H), 7.63 (m, 2H), 7.53 (m, 3H), 7.25 (m, 1H), 6.81 (m, 1H), 6.77 (d,1H, J=8.0 Hz), 6.70 (s, 1H), 5.53 (d, 1H, J=16.0 Hz), 5.48 (d, 1H,J=16.0 Hz), 3.92 (sextet, 1H), 2.85 (d, 2H, J=8.0 Hz), 1.12 (d, 3H,J=8.0 Hz). ¹³C NMR (125 MHz, CD₃OD) δ 159.8, 136.9, 136.3, 133.3, 131.8,131.0, 130.5, 130.4, 129.7, 129.0, 119.8, 117.0, 115.7, 67.9, 52.3,33.3, 23.8.

The synthesis schemes, processes and reagents for the production ofother compounds of the present invention will be readily apparent to theskilled addressee based on the above information, commercially-availablereagents and routine knowledge in the field of organic chemistry andcompound synthesis.

Example 2—In Vivo Experiments

Fourteen week old spontaneous hypertensive rats (SHR; Australian AnimalResources Centre, WA) on a 2.2% salt diet (Glenn Forrest Stockfeeders,WA) were randomized to the following treatment groups: 14-week control,or VB0002 infusion (20 pmol/kg/min in 20% DMSO) or vehicle controlinfusion (20% DMSO) for 4 weeks. VB0002 and vehicle control infusionswere via Alzet osmotic minipump, which was inserted under generalanaesthesia (Isoflurane 3% in oxygen) at 14 weeks.

Fourteen week old spontaneous hypertensive rats on a 2.2% salt diet werealso randomized to the following treatment groups: 14-week control, orVB0003 administration (10, 100 or 500 pmol/kg/min in 5% ethanol), VB0005administration (100 pmol/kg/min in 5% ethanol) or drinking solution (5%ethanol) administration for 4 weeks.

The 14-week control group were anaesthetized using isoflurane (3%)delivered in oxygen, then had blood sampled and hearts and kidneysharvested for quantitation of fibrosis. The remaining groups wereweighed and had blood pressure measured by tail cuff plethysmography(ADI Instruments) twice weekly for a further 4 weeks. After 4 weekstreatment, rats were anaesthetized and samples collected as per the14-week control group. Results are mean±sem for n=5 rats per group.

For quantitation of fibrosis, tissue slices ≤3 mm thick were fixed in10% buffered formalin for 24 hours, processed and embedded in paraffin.Three μm transverse sections were stained using Masson's Trichrome. Aminimum of 20 random fields at 40× magnification from transversesections (5 at each of 2 levels) were digitized. The degree of fibrosiswas determined as a percent of field area of each digitized image usingImage-Pro Plus V.5 (Media Cybernetics, Bethesda, Md., USA), and thenaveraged to determine the level of fibrosis for each rat.

Systolic blood pressure in rats treated with VB0002, VB0003 and VB0005was reduced compared to 18 week controls (FIGS. 8 and 9 ), showing thatthese compounds are effective in lowering blood pressure.

Myocardial fibrosis in rats treated with VB0002 at 20 pmol/kg/min wasreduced compared to 14 week controls and 18 week controls (FIG. 10 ),showing that this compound reduces the development of myocardialfibrosis and reverses established myocardial fibrosis.

Myocardial fibrosis in rats treated with VB0003 at 10, 100 and 500pmol/kg/min was reduced compared to 18 week controls (FIG. 11 ), showingthat these compounds reduce the development of myocardial fibrosis.Myocardial fibrosis in rats treated with VB0003 at 100 and 500pmol/kg/min was reduced compared to 14 week controls (FIG. 11 ), showingthat these dosages of the compound reverse established myocardialfibrosis.

Myocardial fibrosis in rats treated with VB0005 at 100 pmol/kg/min wasreduced compared to 14 week controls and 18 week controls (FIG. 10 ),showing that this compound reduces the development of myocardialfibrosis and reverses established myocardial fibrosis (FIG. 12 ).

The invention claimed is:
 1. A compound of the formulae:

wherein: X is selected from the group consisting of:

R₁ to R₉ are independently C, N, O or S; R₁₀ is independently selectedfrom C₁₋₆alkyl, halo, C₀₋₆alkyl carboxylic acid, amino, hydroxy andC₁₋₆alkoxy; Y is A, CH₂-A or CH=A; A is selected from:

Z is selected from the group consisting of:

R₁₁ is independently selected from halo, alkyl, hydroxy, amino andsubstituted amino; R₁₂, R₁₄ and R₁₅ are independently C, CH, CH₂, O, N,NH or S; R₁₃ is C, CH, CH₂, N, NH, C—CF₃, CH—CF₃ or C═O; m is 0, 1, 2,3, 4 or 5; and n is 0, 1, 2, 3 or 4, or a stereoisomer orpharmaceutically acceptable salt thereof.
 2. The compound, or astereoisomer or pharmaceutically acceptable salt thereof, according toclaim 1 wherein R₁₀ is independently selected from —CH₃, —C(O)OH, —F,—NH₂, —OH and —OCH₃.
 3. The compound, or a stereoisomer orpharmaceutically acceptable salt thereof, according to claim 1, whereinR₅ to R₉ are independently C or N.
 4. The compound, or a stereoisomer orpharmaceutically acceptable salt thereof, according to claim 1, whereinthe C₀₋₆alkyl carboxylic acid is carboxylic acid.
 5. The compound, or astereoisomer or pharmaceutically acceptable salt thereof, according toclaim 1, wherein R₁₁ is halo selected from the group consisting of F,Cl, Br and I.
 6. The compound, or a stereoisomer or pharmaceuticallyacceptable salt thereof, according to claim 1, wherein R₁₁ issubstituted amino of the formula —NHR₁₆ and wherein: R₁₆ is selectedfrom —CN, —SO₂(R₁₇)_(a)R₁₈ and —CO(R₁₇)_(a)R₁₈, a is 0 or 1, R₁₇ isselected from —NH— and —O—, and R₁₈ is selected from —H, —CH₃, —CH₂CH₃,—CH₂OH and —CH₂CH₂OH.
 7. The compound, or a stereoisomer orpharmaceutically acceptable salt thereof, according to claim 1, whereinR₁₁ is substituted amino selected from the group consisting of—NHSO₂CH₃, —NHCOH, —NHCONHCH₃, —NHCONHCH₂CH₃, —NHSO₂NHCH₃,—NHSO₂NHCH₂CH₃, —NHCOCH₃, —NHCOOCH₃, —NHCOOCH₂CH₂OH, —NHCONH₂ and —NHCN.8. The compound, or a stereoisomer or pharmaceutically acceptable saltthereof, according to claim 1, wherein R₁₁ is alkyl selected from thegroup consisting of methyl, ethyl, propyl, butyl and pentyl.
 9. Thecompound, or a stereoisomer or pharmaceutically acceptable salt thereof,according to claim 1, wherein the compound is selected from the groupconsisting of:


10. The compound, or a stereoisomer or pharmaceutically acceptable saltthereof, according to claim 1, wherein the compound is selected from:


11. A pharmaceutical composition comprising a compound, or astereoisomer or pharmaceutically acceptable salt thereof, according toclaim 1 and a pharmaceutically-acceptable excipient.
 12. A method forthe therapeutic treatment of: hypertension or prehypertension in asubject; or fibrosis in a subject; or hypertension and fibrosis in asubject; or prehypertension and fibrosis in a subject, the methodcomprising administering to the subject a compound, or a stereoisomer orpharmaceutically acceptable salt thereof, according to claim
 1. 13. Themethod according to claim 12 wherein the fibrosis selected frommyocardial fibrosis, kidney fibrosis, liver fibrosis and lung fibrosis.